Abstract: Rationale: Patients with epilepsy often have several seizure triggers with sleep deprivation (SD) being extremely common. The resulting ?breakthrough? seizures can occur regardless of the type of epilepsy or whether they are well-controlled or not, causing a huge psychosocial impact and even sudden death. A major knowledge gap exists, not only in understanding why and how SD exacerbates seizures but also in how best to treat/prevent these harmful interactions. Hypothesis: Based on prior studies and our preliminary observations we chose to focus on altered GABAergic tonic inhibition (GTI) in the hippocampus as the main mechanism by which SD leads to increased network excitability and seizure exacerbation. Our hypotheses are that i) SD-induced seizure exacerbation is due to increased network excitability in the hippocampus that occurs through reductions GTI and ii) Selective activation of ? subunit-containing GABAA receptors rescues SD- associated altered GTI and network excitability, and prevents seizure exacerbation. Research Design: We will test the above hypotheses in rodent models of genetic (Kv1.1-/-) and induced (repeated low dose kainate) epilepsy by sleep depriving epileptic mice (4 hours/day x 5 days using gentle handling techniques), and examine: i) seizure/interictal spike frequency using continuous video-EEG recordings ii) GTI and network excitability using whole-cell patch clamp and field potential recordings from brain slices of same animals that have EEG recording; iii) whether selective activators of ? subunit-containing GABAA receptors (Gaboxadol) can rescue the altered GTI/network excitability and prevent seizure exacerbation induced by SD. The degree of change in GTI with SD in different groups and the correlation to population spike dynamics and seizure/interictal spike frequency will be analyzed. To further understand whether reduced GTI is mechanistically linked to increased network excitability, we will also examine population spike changes in response to blockers of GTI (L655,708) in hippocampal slices. As control experiments, we will conduct tandem studies with a dual orexin receptor antagonist (DORA) (eg., almorexant) that neither directly affects GTI nor has any anticonvulsant effects. Additional studies in Kv1.1-/- mice will also be done to determine: a) whether enhancing phasic inhibition (but not GTI mediated by ? subunit-containing receptors) with zolpidem (5mg/kg i.p immediately after each SD) prevents SD-induced exacerbated seizures and b) if survival can be prolonged in non-SD mice, after daily administration of gaboxadol and DORA starting at P30. Future directions/Population Impact: The findings of this study could not only advance our understanding of the molecular underpinnings of SD-induced seizure exacerbation in epilepsy, but also on whether sleep restoration with specific drugs prolongs survival in a mouse model that recapitulates SUDEP (Kv1.1-/-). The observations can potentially connect research from the bench to the bedside to improve the quality of life of patients and potentially lower epilepsy-related mortality.